Colorectal cancer and colitis-associated cancer, a subtype of colorectal cancer associated with inflammatory bowel disease (IBD), are major health risks and leading causes of death. Colon carcinogenesis is generally regarded as being composed of multiple stages of sequential mutations of some oncogenes and tumor suppress. The most common initiating event of colorectal carcinogenesis is mutation of the adenomatous polyposis coli (APC) gene, which leads to activation of the Wnt/beta-catenin pathway. Identification of molecular events that regulate tumorigenesis after APC loss is important for understanding the mechanism of colon carcinogenesis and therapeutic development. Wnt signaling via beta-catenin is critically important in regulating normal crypt cell homeostasis and is dysregulated in colon carcinogenesis. Almost all colorectal cancers exhibit mutation of either APC or beta-catenin, which leads to the blockade of phosphorylation by GSK-3, resulting in &#946;-catenin stabilization and enhanced Wnt/beta-catenin signaling. During the course of tumorigenesis, additional mutations (such as KRAS and TP53) are usually acquired. It has long been recognized that chronic IBD increases the risk of colorectal cancer. The transcription factor NF-kappa-B has also been shown to be a key factor linking inflammation and immunity to cancer development and progression. A recent study showed that NF-kappa-B could enhance Wnt signaling, leading to the dedifferentiation of epithelial non-stem cells into tumor-initiating cells. However, clearly defining the regulatory mechanism of Wnt signaling and its role in colon carcinogenesis continues to present a challenge. Olfactomedin 4 (OLFM4) is an evolutionarily conserved glycoprotein that belongs to an olfactomedin family. It was first cloned in human hematopoietic myeloid cells and is also abundantly expressed in intestinal crypts. It affects a diverse set of cellular processes, including proliferation, differentiation, apoptosis, adhesion, and innate immunity against bacterial infections. OLFM4 transcription is regulated by PU.1, NF-kappa-B, Notch, and retinoic acids. Its expression is also regulated epigenetically through promoter methylation. OLFM4 expression is upregulated in human IBD, which comprises ulcerative colitis and Crohns disease. OLFM4 interacts with NOD1 and NOD2, which are intracellular sensors for bacterial infection that have been found to be associated with Crohns disease. A recent study has demonstrated that OLFM4 is a robust marker for intestinal Lgr5-positive stem cells. OLFM4 tends to be overexpressed in early-stage colon cancer, but reduced or lost in advanced stages of the disease.These observations suggest that OLFM4 may play a role in the transition from colon adenoma to dysplastic tumors, but its biological function in the intestine remains to be determined. Here we show that Olfm4 deletion induced colon adenocarcinoma in the distal colon of ApcMin+ mice. Mechanistically, we found that OLFM4 is a target gene of the Wnt/beta-catenin pathway and can downregulate beta-catenin signaling by competing with Wnt ligands for binding to Frizzled receptors, as well as by inhibition of the Akt-GSK3&#946; pathway. We have shown that both Wnt and NF-kappa-B signaling were boosted in tumor tissues of Apc Olfm4 double-mutant mice. These data establish OLFM4 as a critical negative regulator of the Wnt/ beta-catenin and NF- kappa-B pathways that inhibits colon-cancer development initiated by APC mutation. In addition, Olfm4 deletion significantly enhanced intestinal-crypt proliferation and inflammation induced by azoxymethane/dextran sodium sulfate (AOM/DSS). Thus, OLFM4 plays an important role in the regulation of intestinal inflammation and tumorigenesis, and could be a potential therapeutic target directed at intestinal malignant tumors.